The capacity to assay hematopoietic progenitor and stem cells in humans and mice, and factors which regulate the growth of these cells, allows us to investigate normal and abnormal hematopoiesis in vitro and in vivo. We believe that negative feedback mechanisms play a role in the physiological regulation of granulocyte-macrophage progenitor cells and are important in the development and progression of acute and chronic leukemia, myeloproliferative and myelodysplastic disorders. We propose to use in vitro and in vivo approaches to study a cell-free inhibitory activity we have recently reported, leukemia associated inhibitory activity (LIA), and which we have now identified as acidic isoferritins. Acidic isoferritins are well-characterized iron-binding glycoproteins which we have available in purified form. The extremely low concentrations needed for action in vitro suggest that it may be physiologically relevant. The increase of acidic isoferritins during leukemia, its suppressive action on normal granulocyte-macrophage progenitor cells and the non-responsiveness of progenitor cells from patients with leukemia to it, suggest it may be involved in the pathogenesis and progression of leukemia and other blood disorders. In vitro assays will be made more sensitive and hematological (cell cultures, viruses), immunological (monoclonal antibodies and rosetting) biophysical (cell sorting, velocity sedimentation, density gradient, adherence, electron microscopy), and biochemical (radioisotopes, radioimmunoassay) procedures will be used to define the mechanisms of production and action of acidic isoferritin-inhibitory activity in vitro. Normal and leukemic mice will be used to determine action in vivo, and significance of acidic isoferritins to disease progression. We will explore means to modulate the production and action of acidic isoferritins in vitro and in vivo, and will determine they may be able to be used as a supplement to chemotherapy treatment protocols. The presence and activity of acidic isoferritins will be correlated with diagnosis and prognosis of patients with leukemia and with significance to remission induction and duration.